Virus infections often lead to pathogenic consequences and disease considerably beyond the acute phase on infection. The significance of persistent infections for human disease processes is only now becoming apparent. In the course of a persistent infection, disease may develop as a consequence of host immune responses against the virus and virus infected cells and/or from virus disruption of cellular functions. At present, there is only limited understanding of the molecular details of persistent virus infection. There have been many suggestions that defective interfering (DI) RNAs may be involved with the establishment and maintenance of persistent virus infections. Although DI RNAs have been linked to persistence in tissue culture systems, there is little information that relates directly to the appearance and function of DI RNAs during infection in vivo. The studies proposed here will examine persistent infections induced in laboratory mice by lymphocytic choriomeningitis virus to determine whether deleted RNAs (i.e., potential DI RNAs) appear and accumulate in persistently infected animals and whether these RNAs alter the normal course of acute infection. A complementary series of experiments will investigate potential regulatory mechanisms that reduce viral gene expression and may mediate the transition from acute to persistence infection. A detailed understanding of the molecular basis of virus persistence in one system will allow conceptual developments for the whole field of virus persistence and may suggest strategies for intervention and eventual clearance of a persistent infection.